Article
作者: Xin, Lei ; Hu, Nan ; Xu, Aiying ; Liu, Xuesong ; Liu, Junhua ; Guo, Yin ; Liu, Xiaoxin ; Hong, Yuan ; Zheng, Zhijun ; Wei, Qiang ; Guo, Yunhang ; Sun, Weihua ; Wang, Zhiwei ; Li, Yong ; Yu, Desheng ; Yang, Shasha ; Guo, Ying ; Liu, Ye ; Zhang, Fan ; Su, Dan ; Wu, Yue ; Qin, Ling ; Zhu, Yutong ; Sun, Hanzi ; Wang, Fan ; Li, Shuran ; Sun, Xuebing ; Wang, Lai ; Shi, Gongyin ; Xue, Hai ; Yang, Xuefei ; Chen, Shuaishuai ; Zhou, Changyou ; Xu, Haipeng ; Yuan, Xi ; Zhang, Taichang ; Song, Xiaomin
The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.